Cyclic GMP-dependent protein kinase (G-PK) has been extensively purified from the guinea pig fetal lung, calf fetal heart and bovine aorta, and their properties studied. It has been shown that cyclic GMP acts (in the presence of substrate protein) by causing dissociation of G-PK holoenzyme to regulatory (cyclic GMP-binding) and catalytic subunit. The free catalytic subunit, however, is not active per se, unless it is complexed with stimulatory modulator. The levels of G-PK, but not those of cyclic AMP-dependent protein kinase (A-PK), were found to be lower in the hypertrophied heart of spontaneously hypertensive rats. It was also shown that the peripheral arteries of the dog were disproportionately richer in G-PK than the veins, with an exception of the pulmonary artery, and atypical arterial tissue exposed to low blood pressure. Creation of femoral arteriovenous fistulae in dogs led to preferential reductions in G-PK activity (as opposed to A-PK activity) both in the proximal and distal arteries, whereas it was elevated in stressed vein distal to the anastomotic site. Changes in G-PK activity appeared to precede gross changes in the vascular structure. It is suggested that the vascular G-PK, may be closely related to peripheral resistance and its regulation.